The overarching goal of this study is to test the role of pain, illicit drug use, and symptoms of depression and anxiety in the misuse of opioids and psychoactive medications within an existing cohort of men who have sex with men (MSM) participating in the Baltimore/Washington, DC site of the Multicenter AIDS Cohort Study (MACS). Pain and commonly co-occurring psychological symptoms of anxiety and depression are sources of considerable distress and disability among MSM. A nationally representative study of HIV-infected persons in the United States found that 67% of patients experienced pain in the prior month. Of particular concern is the high prevalence of painful peripheral neuropathy which is associated with the long-term use of neurotoxic antiretroviral therapy. Neuropathic pain is especially difficult to treat and patients may misuse opioids as well as psychoactive medications seeking relief. Despite guidelines recommending the use of opioids for pain and psychoactive medications for psychological symptoms, the risk factors for the misuse of these medications among MSM are poorly understood. Existing research has largely been cross-sectional and therefore limited in identifying predictors of prescription drug misuse. This gap has hampered efforts to balance the need to treat distressing symptoms of pain, anxiety, and depression with concerns over misuse. To address this gap, the proposed project will use a prospective, longitudinal design to test the importance of key risk factors for misuse of opioids and psychoactive medications. These risk factors will include pain, particularly painful peripheral neuropathy, symptoms of anxiety and depression, and illicit drug use. The project Specific Aims are: 1) To quantify the associations among these risk factors over time;2) To quantify the relative strength of these risk factors in predicting opioid misuse;and 3) To quantify the associations among illicit drug use, the misuse of opioids and the misuse of psychoactive drugs, as well as the extent to which these relationships are partially explained by pain and symptoms of anxiety and depression. Structural equation modeling (SEM) will be used to address the study aims by allowing the simultaneous quantification of these complex direct and indirect relationships among the study variables. This research is innovative in that we will test a conceptual model focused on the dynamic impact of pain, illicit drug use and symptoms of anxiety and depression on prescription drug misuse over time. This study will advance NIDA's mission of bringing the power of science to bear on drug abuse and addiction by identifying modifiable risk factors that may be the focus of targeted interventions to reduce the risk of prescription drug misuse while effectively managing pain and symptoms of anxiety and depression in MSM. Statement: The findings from this project will assist clinicians in the management of pain and associated psychological symptoms of anxiety and depression by identifying important risk factors for the misuse of opioids and psychoactive medications among MSM. The identification of modifiable risk factors will lay the foundation for targeted interventions to improve the treatment of pain including painful peripheral neuropathy and psychological symptoms of anxiety and depression in MSM while limiting the harmful effects of prescription drug misuse.